While many compounds are known to be useful as pharmacologically active substances, some of them have relatively short biological half lives and must be administered several times a day in order for their full action to be exhibited. However, a decrease in the number of administrations will not only reduce the burden on the patient but will also increase his compliance and thus provide greater therapeutic effects. In order to meet this requirement, medicines must release their active ingredients slowly so that they maintain effective levels in the blood for a prolonged period of time. In addition, if the active substance of a drug can be released a predetermined time after its administration, it becomes possible to allow a larger amount of the active substance to be released at a particular site of an organ such as a digestive tract, thereby producing enhanced therapeutic effects.
Therefore, the principal object of the present invention is to provide a pharmaceutical agent which is so designed that it will either slowly release its active substance over time or release the active substance a predetermined time after its administration.
Various techniques have been proposed for preparing slow-release pharmaceutical agents that are capable of retaining the concentrations of their active substances in the blood for a prolonged period of time. Most of the slow-release pharmaceuticals so far proposed employ a variety of high-molecular weight materials which include: hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, pullulan, gelatin, collagen, casein, agar, gum arabic, dextrin, ethyl cellulose, methyl cellulose, chitin, chitosan, mannan, carboxymethylethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, sodium alginate, poly(vinyl alcohol), cellulose acetate, poly(vinylpyrrolidone), silicone, poly(vinyl acetal) diethylamino acetate and albumin [see Sustained and Controlled Release Drug Delivery Systems, Marcel Dekker, Inc., 1978; Yakkyoku (Pharmacy), vol. 35, No. 2, pp 575-583, 1984; and Japanese Patent Public Disclosure No. 62521/1984].
The use of the above-listed high-molecular weight materials in manufacturing slow-release pharmaceuticals involves several problems: (1) many high-molecular weight materials, particularly those which are soluble in water, have such a high moisture content that the pharmacologically active substances incorporated therein are liable to suffer decomposition, such as by hydrolysis, and often fail to withstand prolonged storage; (2) high-molecular weight material have certain distributions in molecular weight and their molecular weight distribution and average molecular weight generally differ from one to another notwithstanding the existence of certain limits to be complied with and, therefore, the slow-release pharmaceuticals employing such high-molecular weight materials will experience considerable variations in drug dissolution rate no matter how strict the quality control is during the manufacturing process; (3) some of the slow-release pharmaceuticals employing high-molecular weight materials are used in the state of being implanted in the human body, but many high-molecular weight materials are not decomposed in the human body at all or are decomposed only slightly, so they must be removed from the human body after they have liberated the pharmaceutically active substance; even the high-molecular weight materials that are decomposable in the human body are in most cases dependent upon the presence of decomposition enzymes if the rate of their decomposition is to be satisfactory, and this also holds for the rate of release of the active substance; furthermore, even the decomposable high-molecular weight materials are not completely decomposed to monomers and there is a high possibility that only a part of them will be decomposed, most of them remaining as polymers and being absorbed by tissues to become a potential antigen that can cause an anaphylactic shock [see Seiyaku Kogyo (Pharmaceutical Factory), vol 3, No. 10, pp. 552-557 (1983); and Kagaku no Ryoiki (Region of Chemistry), Special Issue, No. 134, pp. 151-157, Nankodo]; (4) in slow-release pharmaceuticals of the matrix type and those wherein the active substances (i.e., drugs) are released through a semipermeable membrane, the drug release rate is so highly dependent on the solubility of the drug that such types of slow-release pharmaceuticals are not suitable for use with sparingly soluble drugs; and (5) pharmaceuticals having coatings of water-insoluble high-molecular weight substances are unable to release the active substance a predetermined time after their administration; water-soluble high-molecular weight substances will immediately swell by an infinite degree and are unable to inhibit the drug release for a prolonged period; enteric high-molecular weight substances are unable to release the drug at pHs below 5.0-5.5 but will immediately release it at higher pHs, and hence are unable to perform time-dependent, not pH-dependent, control of the drug release.
The present inventors conducted various studies in order to develop a process for preparing a slow-release pharmaceutical agent that is free from the aforementioned problems of the prior art products. As a result, the present inventors unexpectedly found that the duration of the sustained release of a pharmaceutically active substance can be extended or its release a predetermined time after drug administration can be realized by employing at least one "slow-release rendering additive" selected from the group consisting of adenine, cystine and tyrosine, all being low-molecular weight substances. Cystine and tyrosine occur in isomeric forms but their effectiveness is independent of whether they are in D-, L- or DL-form